PROJECT SUMMARY The long-term objective of this research program is to improve the care of patients suffering from acute ischemic stroke secondary to large vessel occlusion. Acute ischemic stroke affects up to 700,000 people a year in the United States and is the fourth leading cause of death. Approximately 10% of acute ischemic stroke patients present with large vessel occlusion which are associated with high rates of long-term morbidity and mortality. As of 2015, mechanical thrombectomy became standard of care for treatment of acute ischemic stroke from large vessel occlusion. Since then, there has been a significant increase in the use of mechanical thrombectomy for acute stroke treatment. Despite high revascularization rates (~80%), 50% of stroke patients still experience poor neurological outcomes. In addition, 20% of patients are not successfully revascularized due to limitations of current revascularization technologies. Rates of clot fragmentation during mechanical thrombectomy are high with most patients having residual tiny distal emboli in the ischemic territory and up to 10% of patients developing emboli in previously unaffected vascular beds due to fragmentation during clot retrieval. High rates of clot fragmentation and failure to remove the clot resulting in poor neurological outcomes suggest that in order to further advance the field of stroke intervention, we must turn our attention to the science of clot. In this R01 program we will embark on a comprehensive study of the histological, physical and imaging characteristics of clot in acute ischemic stroke with the ultimate goal of studying the efficacy of various revascularization strategies on different clot phenoytpes so that care of acute ischemic stroke patients can be improved. We propose a methodical approach to the study of clot in stroke. Our first aim is to characterize the histological characteristics of clots from a large sample of acute ischemic stroke patients from multiple institutions. Data from this registry will then be used to 1) identify clot phenotypes which will be made for further in vitro study and 2) identify histologic characteristics that are more commonly present in clots prone to fragmentation or difficult to remove clots. Our second aim is to identify imaging biomarkers to identify difficult clots by performing in vitro imaging of the clot phenotypes identified in the first aim. Our third aim is to determine which revascularization techniques are associated with superior outcomes when treating each clot phenotype. This will be performed using an in vitro flow model which replicates the physiological conditions of acute ischemic stroke in humans. If successful, this translational research program will directly improve patient outcomes by helping the stroke community better identify difficult to treat clots and provide data on which revascularization techniques are best suited for clots which are prone to fragmentation or difficult to remove.